Modulating T cell responses to antigens in "humanized" HLA-DR transgenic mice

dc.contributor.advisorForsthuber, Thomas G.
dc.contributor.authorDixit, Aakanksha
dc.contributor.committeeMemberCardona, Astrid
dc.contributor.committeeMemberGuentzel, Neal
dc.descriptionThis item is available only to currently enrolled UTSA students, faculty or staff. To download, navigate to Log In in the top right-hand corner of this screen, then select Log in with my UTSA ID.
dc.description.abstractMultiple sclerosis (MS) is a CD4 + T cell mediated autoimmune disease. It affects every 1 in 700 people in the world. There is no cure for this disease but treatments are available to control the various symptoms and to prevent progression of the disease. The major histocompatibility complex (MHC) class II plays a crucial role in the onset of the disease. These molecules present self peptides to auto-reactive T cells, thereby leading to the induction of MS. To counteract this problem compounds were designed which specifically bound to MHC class II molecules and modulated the immune response by autoreactive T cells to either silence these T cells, or prevent their activation altogether. This was accomplished by modulating the amino acids (aa) of the self peptides to either increase their binding, or by modulating them such that they blocked the MHC binding site to prevent T cell activation. The first class of high affinity analogs of the native peptide is called superagonist. In this study we analyzed the T cell responses that these analogs produced in humanized HLA-DR transgenic mice. It was found that some of the superagonist analogs specific to MBP 115-126 could suppress Th17 immune responses, but not IFN-g responses. The alternative approach of generating superagonist random libraries was not as efficient in suppressing T cell responses against the native peptide in the transgenic mice. In contrast, the peptide designed to inhibit binding of self-peptides to the MS-associated MHC class II molecule HLA-DR2 (DRB1*1501), was highly successful in treating disease in an animal model of MS termed experimental autoimmune encephalomyelitis (EAE). Based on the results we propose that the DR2-blocker PV267 may restrict autoreactive T cells to the peripheral immune system and may not allow them to enter the central nervous system, thus inhibiting myelin destruction, the root cause of MS.
dc.description.departmentIntegrative Biology
dc.format.extent75 pages
dc.subjectDR2 inhibitor
dc.subjectPV 267
dc.subjectT cell responses
dc.subject.classificationMolecular biology
dc.titleModulating T cell responses to antigens in "humanized" HLA-DR transgenic mice
dcterms.accessRightspq_closed Biology of Texas at San Antonio of Science


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